Nuclear receptors (NR) are ligand-regulated transcription factors that play diverse role in the expression of target genes associated with physiological processes such as cell differentiation, development, metabolism and immunity. All members of the nuclear receptors super family are multi domain proteins. Majority of the nuclear receptors contain the four functional domains, namely N-terminal “A/B domain”, DNA-binding domain or “C domain”, highly variable hinge or “D domain”, and C-terminal ligand-binding domain (LBD) or “E domain” Several NRs contain a highly variable C-terminal F domain.
Retinoid-related orphan receptors (RORs) are the subfamily of nuclear receptors. The ROR subfamily contains three isoforms, namely RORalpha (RORα), RORbeta (RORβ) and RORgamma (RORγ), which are also referred to as NR1F1, NR1F2 and NR1F3 respectively. The RORα, RORβ and RORγ function as ligand dependent transcription factors and recent research studies suggest that RORs may be potential therapeutic targets for treatment of various diseases. Each of the ROR are encoded by a distinct gene RORA, RORB and RORC respectively and each ROR gene generates several isoforms, differing only in their N-terminal “A/B domain” Retinoid-related orphan receptors contain four principle domains as shared by the majority of the nuclear receptors. The RORs display significant sequence similarity. For RORα (α1-4), four isoforms have been identified, and RORβ gene is expressed in only one isoform in humans, whereas for RORγ, two isoforms have been identified namely RORγ1 and RORγ2. The isoform “RORγ2” is also known as RORγt.
RORγt is exclusively detected in a few distinct cell types of the immune system, for instance, in thymus (Journal of Experimental Pharmacology, 2012, 4, 141-148; Nuclear Receptor Signaling, 2009, 7, 1-32) while RORγ1 is expressed in many tissues, including thymus, lung, liver, kidney, skeletal muscle, adipose tissue and skin. The RORγt has been identified as a key regulator of T helper 17 (Th17) cells differentiation. It is reported that RORs have critical regulatory roles in thymopoiesis, development of secondary lymphoid tissues, and Th17 cell differentiation are highly relevant to a variety of immune responses and inflammatory disorders, including autoimmune diseases and asthma (Nuclear Receptor Signaling, 2009, 7, 1-32; International Immunopharmacology, 2011, 11, 536-542).
Th17 cells are a subset of T helper cells producing interleukin-17 (IL-17). They are developmentally distinct from Th1 and Th2 cells, which are the other two subsets of T helper cells. Th17 cells have been shown to play a critical role in several inflammatory disease and autoimmune diseases (Immunological Reviews, 2008, 223, 87-113). In addition, the studies have shown that Th17 cells have key pro-inflammatory roles in cancer and a variety of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), inflammatory bowel disease (IBD) and graft versus host disease (Cancer research, 2011, 71, 1263-1271; Cell, 2006, 1121-1133; Journal of Clinical Investigation, 2006, 1310-1316; Blood and Marrow Transplantation, 2012, 18, S56-S61).
Th17 cells/IL-17 plays a key role in the pathogenesis of asthma. In asthmatic patients, both RORγt and IL-17A expression levels have been shown to be increased in sputum, lung, and bronchoalveolar lavage (BAL) fluids and peripheral blood and these levels directly correlate with disease severity. In addition to IL-17A, a recent study have shown that a cytokine of the IL-17 family namely IL-17F, may have a crucial role in allergic airway inflammation and hence, have key implications in airway diseases, such as asthma (Respiratory Research, 2010, 1-11).
The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Th17 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (Journal of Experimental Medicine, 2008, 205, 1517-1522; Cellular and Molecular Immunology, 2010, 7, 182-189). Also, during the disease process Th17 cells are activated and are responsible for recruiting other inflammatory cells types, particularly neutrophils, to mediate pathology in the target tissues.
Several studies suggest that RORγt plays a vital role in metabolic disorders and autoimmune diseases (Journal of Experimental Pharmacology, 2012, 4, 141-148). Metabolic disorders are the disorders or defects that occur when the body is unable to properly metabolise carbohydrates, lipids, proteins, or nucleic acids. Most metabolic disorders are caused by genetic mutations that result in missing or dysfunctional enzymes that are needed for the cell to perform metabolic processes. Examples of metabolic disorders include obesity, excessive body fat, hyperlipidemia, hyperlipoproteinemia, hyperglycemia, hypercholesterolemia, hyperinsulinemia, insulin resistance, glucose intolerance, and diabetes mellitus particularly type 2 diabetes. RORs were shown to affect the expression of several genes involved in steroid, bile acid, and xenobiotic metabolism, suggesting that RORs are promising targets for the treatment of obesity-associated insulin resistance and metabolic disease (EMBO Mol. Med. 2011, 3(11), 637-651.
It is reiterated here that RORγt has also been shown to play a critical role in the differentiation of Th17 cells (Cell, 2006, 1121-1133, International Immunopharmacology, 2011, 11, 536-542). RORγt deficiency results in diminished Th17 activity and severely reduced expression of IL-17.
Various PCT published patent applications, WO2014028669, WO2013160418, WO2013085890, WO2013029338, WO2012100732, WO2012100734, WO2012139775, WO2012027965, WO2012028100 and WO2012064744 disclose compounds which are reported to be modulators of RORγ.
Pentacyclic triterpenes have a range of unique and potentially usable biological effects. In fact, there is a growing interest in the elucidation of the biological roles of the triterpenoid compounds. From biological point of view, the most important pentacyclic triterpenoid type compounds are ursane, oleanane, lupine and taraxasterane. Among these triterpenoid compounds, ursolic acid is known to possess a wide range of biological activities including anti-oxidative, anti-inflammatory and anticancer activities (Nutr. Food Res., 2008, 52, 26-42 and Biochem. Pharmacol. 2013, 85, 1579-1587). It is also reported that ursolic acid suppresses IL-17 production by selectively antagonizing the function of RORγt protein (J. Bio. Chem. 2011, 286(26), 22707-22710). A variety of structure modifications of UA has also been conducted. Three series of UA derivatives and their inhibitory activity on serotonin biosynthesis using RBL2H3 cells were evaluated (Journal of Medicinal Chemistry, 2014, 57, 4692-4709).
Thus, in consideration of various roles of RORγ and IL-17 in the pathogenesis of various diseases or disorders, compounds that modulate the activity of RORγ and inhibit IL-17 expression, will have therapeutic potential in treating diseases or disorders mediated or implicated by RORγ or IL-17. The inventors of the present invention have developed the compounds that function as modulators of RORγ and inhibitors of IL-17. Accordingly, the compounds of the present invention find use in the treatment of diseases mediated by RORγ or IL-17.